Children with genetic disorders are especially vulnerable to psychiatric illness. Even in typically developing children, negative early life experiences have been shown to increase hypothalamic-pituitary-adrenal (HPA) axis activation with associated neuroendocrine and immunological disregulation with potentially deleterious effects on neural development. Chromosome 22q11.2 deletion syndrome (22q11.2DS) occurs in 1:4000 live births and along with a multitude of possible phenotypic effects, imparts a 25 fold increased risk for schizophrenia in adulthood. Several converging lines of evidence are highly suggestive of the possible role of stress and anxiety as a modulating factor that may increase the likelihood that a child with 22q11.2DS develops a psychotic disorder in young adulthood and at the very least negatively impacts the quality of the child's life. Shyness and social impairment is very common in children with 22q11.2DS. From an early age, children with the deletion often have extensive medical concerns and as the child ages and enters the school system, his or her cognitive and social deficits begin to become more apparent in the context of increasing social and academic expectations. This is not a simplistic cause and effect relationship but rather could be thought of as multiple negative hits to an already challenged developing system and these factors may also set the stage for further stressors. In the K99 and into the R00 phases of the award, I will be measuring the physiological and psychological correlates of stress and anxiety in children with 22q11.2DS and relating those measures to metrics of immunological function, changes in the growth and function of brain structures (e.g. hippocampus and amygdala) associated with both the effects of chronic stress and a diagnosis of schizophrenia. Into the R00 phase I will be conducting longitudinal measures on these children to better determine causal relationships between stress and risk of psychosis and more practically increase quality of life. This research applies well-established methods of measuring the stress and its associated physiological effects but these methods are completely novel with regards to this population of children with 22q11.2DS PUBLIC HEALTH RELEVANCE: Narrative Stress and anxiety have real effects on health but little is known about its reciprocal effects on development in children with genetic disorders, especially children with the most common genetic microdeletion in humans resulting in chromosome 22q11.2 deletion syndrome. Anxiety in children is amenable to treatment which decreases the likelihood of psychiatric problems in adulthood where support opportunities may be limited and the impact on the healthcare system is great. These methods are also amenable to studying other populations with high levels of anxiety such as children with Fragile X and those with autism spectrum disorder.